This research has focused on the development of novel treatments for spinal cord injury (SCI). We have worked to find methods to promote functional recovery as well as to alleviate neuropathic pain (NP). We have studied the role of cyclooxygenase 2 (COX2) inhibitors on functional recovery following acute SCI, the effect of stem cell and olfactory nerve ensheathing cell transplantation on recovery of function following SCI, and the influence of folic acid metabolism on functional recovery following SCI. Our studies have included genetic analysis of both the acute and chronically injured spinal cord using Genechip as well as RTPCR technologies. We have reported genetic changes observed in the dorsal column of the spinal cord of rats subjected to a loose ligation of the sciatic nerve, and found interesting alterations in the expression of several genes known to play a role in nociception. These alterations resolved as the behavioral evidence of allodynia resolved. We have established an rat model for the assessment of “thermal hyperalgesia” a behavior following spinal cord injury and intend to use this model to perform an in depth analysis of the factors responsible for the development of neuropathic pain following spinal cord injury.

Several research papers on various aspects of SCI mechanisms and therapeutic applications have been published. Some of these publications evaluated WNK1, cation-dependent chloride transporters activation (NKCC1) and inhibition by bumetanide, cannabinoid receptors specially CB2 (anti-hyperalgesic effect of WIN 55,212-2), anti-hyperalgesic effects of bradykinin (B1) and vanilloid-1 (TRPV1) receptor antagonists, rolipram (specific PDE4 inhibitor) effect on thermal hyperalgesia, cyclooxygenase-2 (Cox2) inhibitor (meloxicam) and PPAR-gamma induction and ghrelin for control of SCI-induced neuropathic pain. I also presented the research findings at six national and three international meetings. I regularly supervise the undergraduate and med students working in the SCI lab. My research expertise encompasses all aspects of the present proposal including induction of SCI, monitoring functional recovery, measurements of neuropathic pain and evaluating the molecular mechanisms. In this project, I will co-supervise the experiments conducted by other scientists, students and research specialists, write the manuscripts and plan the day to day research work of the lab. Recently submitted research papers including "Persistent phosphorylation of NKCC1 and WNK1 in the epicenter of the spinal cord following contusion injury

Recently in a rat model of contusion SCI (cSCI) we have reported expression and activity of matrix metalloproteinases (MMPs; MMP9 and MMP2) in spinal cord injured rats. As an upstream modulator of inflammatory cytokine production, MMPs cleave the pro-form of cytokines into the active form and play a significant role in regulating the components of the extra-cellular matrix surrounding the cell via tissue remodeling, signaling, and inflammation within the nervous system. We have characterized the expression and activity levels of MMP9 in the acute phase and MMP2 in the late phase, respectively. SCI-induced NP and its association with the cellular and molecular changes in the interactions between extracellular signaling kinase, β-catenin, and MMP2. Wnt/ β-catenin signaling controls the development of the blood-brain barrier, which suggests its use as a therapeutic agent in limiting damage to the blood spinal cord barrier. Our preliminary data suggests that the initial down-regulation of phosphorylated extracellular signaling kinase may lead to the up-regulation of both β-catenin and MMP2 in SCI and neuropathic pain. These findings support the idea that MMP9 and MMP2 be used as a potential therapeutic target for SCI treatment.

We also have ongoing collaborative projects underway with members of the University of Wisconsin. This research team includes researchers from the department of neurological surgery as well as Anesthesiology department of medical school. These experiments are designed to assess the novel mechanisms of cell-based and gene-based therapy of SCI/NP. In this study we hypothesize that early inhibition of MMP9 and/or delayed enhancement of MMP2 activity in the spinal cord will improve functional recovery after injury. The study will be aimed at: testing whether the early inhibition of MMP9 will alleviate the infiltration of inflammatory cells, diminish the disruption of the blood spinal cord barrier (BSCB), and improve functional recovery using TIMP1-lacZ-neutrophil therapy. Other projects are designed to determine whether MMP-9 produced by macrophages induce myelinated axon damage using TIMP1-lacZ-macrophage therapy. Finally, we are determining whether the late increase in MMP2 enhances functional recovery following SCI using MMP2-lacZ-macrophage therapy.

Clinical Research Interests:

Evidence Based Guidelines:

Dr. Resnick has published numerous clinical practice guidelines and remains involved in the development and review of such documents through his role as a member of the Congress Of Neurological Surgeon’s Guidelines Committee, Director of the North American Spine Society Research Council, and a member of the AANS/CNS Joint Guidelines Committee. The practice and teaching of evidence based neurosurgery and spinal surgery are a major part of his academic mission.

Comparative Effectiveness Research:

A pioneer in the utilization of registry based data collection to provide important clinical information to clinicians, Dr. Resnick has been instrumental in the design and development of the Neuropoint SD project (through NPA), as well as the N2QOD database, the WISPOS project, and the NASS Registry. Currently, grant supported clinical outcomes research is investigating the efficacy of surgical versus non-surgical management of common lumbar spine disorders.

Sun D, Hasbargen T, Miranpuri G, Lin L, Resnick DK: Role of NKCC1 and KCC2 in the development of neuropathic pain following spinal cord injury. Annals of the New York Academy of Sciences 1198: 168-172, 2010.